Abstract:

Claims:

1. A method of treating pain due to arthrosis in a subject in need
thereof, said method comprising administering to said subject a
pharmacologically effective amount of tapentadol.

2. A method according to claim 1, wherein the mean serum concentration of
tapentadol following twice-daily administration over a period of at least
three days is on average at least 5.0 ng/ml.

3. A method according to claim 1, wherein the mean serum concentration of
tapentadol in at the most 50% of the patient population following
twice-daily administration over a period of at least three days is on
average less than 5.0 ng/ml.

4. A method according to claim 1, wherein the mean serum concentration of
tapentadol in at the most 50% of the patient population, following
twice-daily administration over a period of at least three days is on
average more than 300 ng/ml.

5. A method according to claim 1, wherein the mean serum concentration of
tapentadol in at least 50% of the patient population, following
twice-daily administration over a period of at least three days is on
average in the range of from 1.0 ng/ml to 500 ng/ml.

6. A method according to claim 1, wherein the tapentadol is administered
in a solid dosage form form.

7. A method according to claim 1, wherein the tapentadol is administered
orally.

8. A method according to claim 1, wherein the tapentadol is administered
twice-daily.

9. A method according to claim 1, wherein the tapentadol is administered
in an amount of 10 to 300 mg.

10. A method according to claim 1, wherein the tapentadol is administered
in a pharmaceutical composition further comprising a pharmaceutically
acceptable carrier.

11. A method according to claim 1, wherein the tapentadol is administered
in pharmaceutical dosage form having a total mass in the range of from 25
to 2.000 mg.

12. A method according to claim 6, wherein said solid dosage form is
selected from the group consisting of tablets, capsules, pellets and
granules.

13. A method according to claim 1, wherein the arthrosis is selected from
the group consisting of gonarthrosis, coxarthrosis and spondylarthrosis.

14. A method according to claim 1, wherein said pain is moderate to strong
pain.

15. A method according to claim 1, wherein said pain is selected from the
group consisting of pain following periods of inactivity, weight-bearing
pain, fatigue-induced pain, periarticular pain on pressure, radiating
pain, pain at rest after spending a long time in the same position,
constant pain, spontaneous pain, pain on movement, night pain, muscular
pain, pain at the end of the range of movement and osseous pain as
spontaneous pain and pain at rest.

Description:

[0002]The invention relates to the use of tapentadol for treating pain due
to osteoarthritis.

[0003]Arthrosis (osteoarthritis, arthrosis deformans) is the most
widespread human joint disease. It is a dynamic, but slow progressing,
degenerative disease of the cartilage and other articular tissue,
particularly in elderly individuals, with intermittent inflammatory
episodes. It may be distinguished from other rheumatic diseases by the
absence of inflammatory parameters, restricted mobility, short-term
articular stiffness and its radiological features.

[0004]Arthrosis or joint wear and tear is joint damage that starts with
the degradation of the articular cartilage. In severe cases, it finally
results in transformation processes in the adjacent bone and the surface
of the joint is destroyed. Therefore, the consequences of the disease are
pain and stiffness of the joint with restricted movement. The joints can
become deformed and are ultimately completely ossified. Arthrosis
generally progresses slowly. As a result, the layer of cartilage becomes
thicker at first and the chondrocytes become more metabolically active.
Changes to the subchondral trabecula result in reduced pressure relief by
the spongy bone. The reparation tissue is subjected to more stress and as
the duration of the disease advances, the equilibrium alters with respect
to destruction. X-rays reveal a narrowing of the articular space and
osteophytes form at the edges. For further details, it is possible, for
example, to refer comprehensively to D Hoffler et al, AVP
Therapieempfehlungen der Arzneimittelkommission der Deutschen
Arzteschaft, Arzneiverordnung in der Praxis, "Degenerative
Gelenkerkrankungen", 2nd Edition 2001; and H Broll et al, CliniCum,
Special Edition September 2001, Konsensus-Statement, "Arthrose-Diagnostik
% Therapie".

[0005]In principle, all joints can be affected by arthrotic changes.
However, most commonly affected are the knee joints (gonarthrosis) and
hip joints (coxarthrosis) which have to bear a great amount of weight.
The disease also frequently occurs in the small vertebral joints
(spondylarthrosis) and in the finger joints. ICD-10 defines arthrosis of
the hips and knees as primary cartilage diseases associated with painful
restrictions of movement (pain following periods of inactivity,
weight-bearing pain) or difficulty in walking. Inflammation, such as
synovitis, can, but does not have to become established.

[0006]Cardinal and early symptoms of arthrosis are pain (early triad: pain
following periods of inactivity, fatigue-induced pain, weight-bearing
pain; late triad: constant pain, night pain, muscular pain). These are
accompanied by restrictions on movement, sensitivity to changes in the
weather and crepitation. The causes of pain with arthrosis are primarily
the result of irritation in the periarticular tendon and ligament
attachments, secondary inflammation, distension of the joint capsule,
reactive effusion, increased pressure in the subchondral bone and
microfractures.

[0007]In early stages, pain only occurs on weight-bearing and subsides if
movement is continued, eg walking further, after a few minutes. When
accompanied by inflammation, these are the typical symptoms of activated
arthrosis: the joint is painful, feels warm and is swollen. Mobility is
restricted. The inflammation often subsides even without treatment. This
explains the generally episodic course of arthrosis: phases of more
severe pain and restricted movement alternate with phases of less pain
and good mobility. The more advanced the signs of wear and tear, the more
rapidly one pain phase succeeds another. Ultimately, the pain is
constant.

[0008]There are a variety of drug-based and non-drug based treatments
available which may be used individually or in combination:

[0014]The European League Against Rheumatism (EULAR) recommends that the
Lequesne Index, ie an overall evaluation by the doctor and the patient's
assessment of the pain, be used to assess the success of a specific
therapy. In addition to an assessment of swelling, reddening and
resistance to pressure of the joint, the FDA recommend that the pain and
function be assessed by means of the
Western-Ontario-McMaster-Universities-Osteoarthritis-Index (WOMAC) and
the Lequesne Index. For drugs used for the symptomatic treatment of
arthrosis, the Osteoarthritis Research Society recommends the scales for
the WOMAC pain score as the main target criterion and the WOMAC mobility
restriction score or Lequesne Index as the secondary target criterion
plus an overall assessment by the doctor and patients.

[0022]Opioid analgesics do not belong to the routine repertoire of drug
treatment for arthrosis, but are unavoidable in certain situations.
However, conventional opioid analgesics sometimes have significant side
effects, in particular constipation, nausea, vomiting, headache,
sedation, fatigue, respiratory depression, allergies and sometimes a drop
in blood pressure. These side effects complicate the long-term therapy of
chronic pain with arthrosis. Therefore, treatment with conventional
opioid analgesics is generally indicated when all other therapeutic
options have been exhausted, for example in the case of patients who
cannot undergo an operation but are suffering extreme pain at rest which
fails to respond to other substances with an analgesic action.

[0023]There is a need for alternative pharmacotherapeutic methods for
arthrosis characterised by effective pain control and a reduced
side-effects profile.

SUMMARY OF THE INVENTION

[0024]Therefore, it was the object of the invention to find compounds that
are effective in pain control with arthrosis and have advantages over
conventional analgesics.

[0025]These and other objects have been achieved by the invention as
described and claimed hereinafter.

[0026]The invention relates to the use of tapentadol to produce a medicine
for treating pain due to arthrosis. It has surprisingly been found that
tapentadol, preferably as a prolonged release (PR) formulation (synonym
of extended release (ER) formulation), ie a formulation with extended
release within the meaning of the European Pharmacopoeia, combines
excellent efficacy for the treatment of pain due to arthrosis with a
reduced side effect spectrum. Extended release is usually understood to
mean modified release which differs from the release of conventional
pharmaceutical forms administered via the same route. The modification of
the release is usually achieved by a special design of the pharmaceutical
form or a special production method.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027]FIG. 1 shows a schematic representation of the titration scheme
adhered to during the investigation of the efficacy of tapentadol for
treating pain due to arthrosis.

[0028]FIG. 2 shows a schematic representation of the efficacy of
tapentadol (100 mg and 200 mg) compared to a placebo and oxycodone.

[0029]FIG. 3 shows a mathematical evaluation of the distribution of the
serum concentration within a patient population following the
administration of different doses of tapentadol.

[0030]FIG. 4 shows a mathematical evaluation of the connection between the
serum concentration of tapentadol and its effect with respect to pain
alleviation in a patient population on the basis of data from various
clinical studies.

DETAILED DESCRIPTION OF THE INVENTION

[0031]Tapentadol, ie
(--)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, is a
synthetic, centrally acting analgesic which is effective in the treatment
of moderate to severe, acute or chronic pain.

[0032]Tapentadol exhibits a dual mechanism of action, on the one hand as a
μ-opioid receptor agonist and on the other as a noradrenaline
transporter inhibitor. In humans, the affinity of tapentadol to the
recombinantly produced μ-opioid receptor is 18-times less than that of
morphine. However, clinical studies have shown the pain-alleviating
action of tapentadol to be only two to three times less than that of
morphine. The only slightly reduced analgesic efficacy with a
simultaneously 18-times reduced affinity to the recombinant μ-opioid
receptor indicates that the noradrenaline transporter inhibiting property
of tapentadol also contributes to its analgesic efficacy. Consequently,
it may be assumed that tapentadol has a similar analgesic efficacy to
that of pure μ-opioid receptor agonists but has fewer of the side
effects associated with the μ-opioid receptor. The compound can be
used in the form of its free base or as a salt or solvate. The production
of the free base is known for example from EP-A 693 475.

[0033]For the purposes of the description, "tapentadol" means
(--)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and the
pharmaceutically acceptable salts and solvates thereof.

[0035]In one preferred embodiment, the medicine is a solid medicinal form.
Preferably, the medicine is formulated for oral administration. However,
other pharmaceutical forms are also possible for example buccal,
sublingual, transmucosal, rectal, intralumbar, intraperitoneal,
transdermal, intravenous, intramuscular, intragluteal, intracutaneous and
subcutaneous.

[0036]Depending upon the formulation, the medicine preferably contains
suitable additives and/or excipients. Suitable additives and/or
excipients for the purpose of the invention are all substances for
achieving galenic formulations known to the person skilled in the art
from the prior art. The selection of these excipients and the amounts to
use depend upon how the medicinal product is to be administered, ie
orally, intravenously, intraperitoneally, intradermally, intramusuclarly,
intranasally, buccally or topically.

[0037]Suitable orally administrable preparation forms include tablets,
chewable tablets, dragees, capsules, granules, drops, juices or syrups;
suitable for parenteral, topical and inhalative administration are
solutions, suspensions, easily reconstituted dry preparations and sprays.
A further possibility are suppositories for use in the rectum. Use in a
depot in dissolved form, a carrier foil or a plaster, optionally with the
addition of means to encourage penetration of the skin, are examples of
suitable percutaneous administration forms.

[0041]The medicinal product and pharmaceutical compositions is performed
with the aid of means, devices, methods and processes which are well
known in the prior art of pharmaceutical formulation, such as those
described for example in "Remington's Pharmaceutical Sciences", ed AR
Gennaro, 17th edition, Mack Publishing Company, Easton, Pa. (1985), in
particular in Part 8, Chapters 76 to 93.

[0042]For example, for a solid formulation, such as a tablet, the active
substance of the medicinal product can be granulated with a
pharmaceutical carrier, eg conventional tablet ingredients, such as maize
starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium
phosphate or pharmaceutically acceptable rubbers, and pharmaceutical
diluents, such as water, for example, to form a solid composition
containing the active substance in a homogeneous distribution. Here, a
homogeneous distribution should be understood as meaning that the active
substance is distributed uniformly throughout the entire composition so
that this can be easily divided into equally effective single dose forms,
such as tablets, capsules, dragees. The solid composition is then divided
into single dose forms. The tablets or pills can also be coated or
compounded in some other way in order to produce a dosage form with
delayed release. Suitable coating means are inter alia polymers acids and
mixtures of polymeric acids with materials such as shellac, for example,
cetyl alcohol and/or cellulose acetate.

[0043]The amounts of tapentadol to be administered to patients vary
depending upon the weight of the patient, the method of administration
and the severity of the disease. In a preferred embodiment, the medicine
contains tapentadol in a amount of 10 to 300 mg, more preferably 20 to
290 mg, even more preferably 30 to 280 mg, most preferably 40 to 260 mg,
as an equivalent dose based on the free base.

[0044]Delayed release of tapentadol is possible from formulations for
oral, rectal or percutaneous administration. Preferably, the medicine is
formulated for once-daily administration, for twice-daily administration
(bid) or for thrice-daily administration, with twice-daily administration
(bid) being particularly preferred.

[0045]The delayed release of tapentadol can, for example, be achieved by
retardation by means of a matrix, a coating or release systems with an
osmotic action (see eg US-A-2005-58706).

[0046]In one preferred embodiment, the mean serum concentration of
tapentadol, following twice-daily administration of the medicine over a
period of at least three days, more preferably at least four days and in
particular at least five days, is on average at least 5.0 ng/ml, at least
10 ng/ml, at least 15 ng/ml or at least 20 ng/ml, more preferably at
least 25 ng/ml or at least 30 ng/ml, even more preferably at least 35
ng/ml or at least 40 ng/ml, most preferably at least 45 ng/ml or at least
50 ng/ml and in particular at least 55 ng/ml or at least 60 ng/ml. This
means that tapentadol is administered over a period of at least three
days twice daily and then, preferably 2 h after the administration, the
serum concentration is measured. The authoritative numerical value is
then obtained as the mean value for all the patients investigated.

[0047]In another preferred embodiment, the mean serum concentration of
tapentadol in at the most 50% of the patient population, which preferably
comprises at least 100 patients, more preferably in at the most 40%, even
more preferably in at the most 30%, most preferably in at the most 20%
and in particular in at the most 10% of the patient population, following
twice-daily administration over a period of at least three days, more
preferably at least four days and in particular at least five days, is on
average less than 5.0 ng/ml, preferably less than 7.5 ng/ml, even more
preferably less than 10 ng/ml, most preferably less than 15 ng/ml and in
particular less than 20 ng/ml.

[0048]In another preferred embodiment, the mean serum concentration of
tapentadol in at the most 50% of the patient population, comprising
preferably at least 100 patients, more preferably in at the most 40%,
even more preferably in at the most 30%, most preferably in at the most
20% and in particular in at the most 10% of the patient population,
following twice-daily administration over a period of at least three
days, more preferably at least four days and in particular at least five
days, is on average more than 300 ng/ml, more preferably more than 275
ng/ml, even more preferably more than 250 ng/ml, most preferably more
than 225 ng/ml and in particular more than 200 ng/ml.

[0049]Preferably, the mean serum concentration of tapentadol in at least
50% or 55% of the patient population, which preferably comprises at least
100 patients, more preferably in at least 60% or 65%, even more
preferably in at least 70% or 75%, most preferably in at least 80% or 85%
and in particular in at least 90% or 95% of the patient population,
following twice-daily administration over a period of at least three
days, more preferably at least four days and in particular at least five
days, is on average in the range of from 1.0 ng/ml to 500 ng/ml, more
preferably in the range of from 2.0 ng/ml to 450 ng/ml, even more
preferably in the range of from 3.0 ng/ml to 400 ng/ml, most preferably
in the range of from 4.0 ng/ml to 350 ng/ml and in particular in the
range of from 5.0 ng/ml to 300 ng/ml.

[0050]In another preferred embodiment, the percentage standard deviation
(coefficient of variation) of the mean serum concentration of tapentadol,
preferably in a patient population of 100 patients, following twice-daily
administration of the medicine over a period of at least three days, more
preferably at least four days and in particular at least five days, is at
the most ±90%, more preferably at the most ±70%, even more
preferably at the most ±50%, at the most ±45% or at the most
±40%, most preferably at the most ±35%, at the most ±30% or at
the most ±25% and in particular at the most ±20%, at the most
±15% or at the most ±10%.

[0051]Preferably, the serum concentrations are average values, produced
from measurements on a patient population of preferably at least 10, more
preferably at least 25, even more preferably at least 50, even more
preferably at least 75, most preferably at least 100 and in particular at
least 250 patients. A person skilled in the art knows how to determine
the serum concentrations of tapentadol. In this context, reference is
made, for example, to TM Tschentke et al, Drugs of the Future, 2006,
31(12), 1053.

[0055]and/or [0056]the medicine tapentadol has delayed release from a
matrix; and/or [0057]contains the medicine tapentadol in a amount of
0.001 to 99.999% by weight, more preferably 0.1 to 99.9% by weight, even
more preferably 1.0 to 99.0% by weight, even more preferably 2.5 to 80%
by weight, most preferably 5.0 to 50% by weight and in particular 7.5 to
40% by weight, based on the total weight of the medicine; and/or
[0058]the medicine contains a pharmaceutically acceptable carrier and/or
pharmaceutically acceptable excipients; and/or [0059]the medicine has a
total mass in the range of from 25 to 2,000 mg, more preferably 50 to
1,800 mg, even more preferably 60 to 1,600 mg, even more preferably 70 to
1,400 mg, most preferably 80 to 1,200 mg and in particular 100 to 1,000
mg, and/or [0060]the medicine is selected from the group consisting of
tablets, capsules, pellets and granules.

[0061]The medicine can be provided as a simple tablet and as a coated
tablet (eg as a film-coated tablet or dragee). The tablets are usually
round and biconvex, but oblong shapes are also possible. Granules,
spheroids, pellets or microcapsules, which are used to fill sachets or
capsules or pressed into disintegrating tablets, are also possible.

[0062]Medicines containing at least 0.001 to 99.999% tapentadol, in
particular low, active doses, are preferred in order to avoid side
effects. The medicine contains preferably 0.01% by weight to 99.99% by
weight tapentadol, more preferably 0.1 to 90% by weight, even more
preferably 0.5 to 80% by weight, most preferably 1.0 to 50% by weight and
in particular 5.0 to 20% by weight. To avoid side effects, it may be
advantageous at the start of the treatment to increase the amount of
tapentadol to be administered gradually (titration) to allow the body to
become accustomed to the active substance slowly. Preferably, tapentadol
is first administered in a dose which is below the analgesically active
dose.

[0063]Particularly preferably, the medicine has an oral pharmaceutical
form, which is formulated for twice-daily administration and contains
tapentadol in an amount of 20 to 260 mg as an equivalent dose based on
the free base.

[0064]According to the invention, tapentadol is used for treating pain due
to arthrosis. Preferably, the arthrosis is selected from the group
consisting of gonarthrosis, coxarthrosis and spondylarthrosis.

[0065]Preferably, the painful arthrosis is an arthrosis as defined by
ICD-10 (International Statistical Classification of Diseases and Related
Health Problems, WHO edition, preferably 2007 version). Preferably, the
arthrosis is selected from polyarthrosis [M15], coxarthrosis [M16],
gonarthrosis [M17], arthrosis of the first carpometacarpal joint [M18],
other arthrosis [M19] and spondylosis [M47]. The references in brackets
refer to the ICD-10 nomenclature.

[0068]If the arthrosis is gonarthrosis [M17], this is preferably selected
from the group consisting of bilateral primary gonarthrosis [M17.0],
other primary gonarthrosis (unilateral or not otherwise specified)
[M17.1], bilateral, post-traumatic gonarthrosis [M7.2], other
post-traumatic gonarthrosis [M17.3] (unilateral or not otherwise
specified), other, bilateral secondary gonarthrosis [M17.4], other
secondary gonarthrosis (unilateral or not otherwise specified) [M17.5]
and unspecified gonarthrosis [M17.9].

[0069]If the arthrosis is arthrosis of the first carpometacarpal joint
[M18], this is preferably selected from the group consisting of bilateral
primary arthrosis of the first carpometacarpal joint [M18.0], other
primary arthrosis of the first carpometacarpal joint (unilateral or not
otherwise specified) [M18.1], bilateral, post-traumatic arthrosis of the
first carpometacarpal joint [M18.2], other post-traumatic arthrosis of
the first carpometacarpal joint [M18.3] (unilateral or not otherwise
specified), other, bilateral secondary arthrosis of the first
carpometacarpal joint [M18.4], other secondary arthrosis of the first
carpometacarpal joint (unilateral or not otherwise specified) [M18.5] and
unspecified arthrosis of the first carpometacarpal joint [M18.9].

[0070]If the arthrosis is other arthrosis [M19], this is preferably
selected from the group consisting of primary arthrosis of other joints
(primary arthrosis not otherwise specified) [M19.0], post-traumatic
arthrosis of other joints (post-traumatic arthrosis not otherwise
specified) [M19.1], other secondary arthrosis (secondary arthrosis not
otherwise specified) [M19.2], other specified arthrosis [M19.8] and
unspecified arthrosis [M19.9].

[0071]Preferably, the pain moderate to strong. In a preferred embodiment,
the pain is selected from the group consisting of pain following periods
of inactivity, weight-bearing pain, fatigue-induced pain, periarticular
pain on pressure, radiating pain (eg knee pain with coxarthrosis), pain
at rest after spending a long time in the same position, constant pain,
spontaneous pain, pain on movement, night pain, muscular pain, pain at
the end of the range of movement, osseous pain as spontaneous pain and
pain at rest.

[0072]Even if the medicines according to the invention exhibit few side
effects only, it may be advantageous, for example, to avoid certain types
of dependency also to use morphine antagonists, in particular naloxone,
naltrexone and/or levallorphan, in addition to tapentadol.

[0073]The invention furthermore relates to a method for treating pain due
to arthrosis, in which tapentadol is administered to a patient in a
pharmaceutically acceptable amount.

[0074]The following examples serve for a further explanation of the
invention but should not be construed as restrictive.

EXAMPLE 1

Objective:

[0075]The efficacy and tolerability of tapentadol with prolonged release
(prolonged release (PR)) and oxycodone HCl with controlled release
(controlled release (CR)) were compared with a placebo in patients with
moderate to severe pain due to arthrosis of the knee.

Methods (Randomised, Placebo-Controlled Double-Blind Study):

[0076]Patients (N=670) were randomly selected and treated over 28 days
twice with tapentadol PR 100 mg, with tapentadol PR 200 mg, with
oxycodone HCl CR 20 mg or with a placebo. The dose was titrated at the
start of the treatment. The primary efficacy endpoint was the average
perception of pain during the preceding 24 hours at the time of the last
medical examination (final visit) based on a visual analog 100-mm sale
(VAS, 0 mm=no pain, 100 mm=worst pain imaginable)).

[0082]In all the groups, gastrointestinal disorders (included nausea,
constipation and vomiting) and disorders of the nervous system (including
tiredness and dizziness) were the most common side effects:

[0083]A mathematical evaluation of the distribution of serum concentration
within a patient population following the administration different doses
of tapentadol is depicted in FIG. 3.

[0084]The clinical data confirm that tapentadol PR 200 mg is effective for
4 weeks in the treatment of moderate to severe chronic pain due to
arthrosis. With respect to gastrointestinal side effects and side effects
associated with the central nervous system, the clinical data indicate
that tapentadol is better tolerated than oxycodone.

[0085]A mathematical evaluation of the connection between serum
concentration of tapentadol and efficacy with respect to the alleviation
of pain in a patient population based on data from various clinical
studies is shown in FIG. 4.

[0086]Patients (N=878) were randomly assigned in a 4:1 ratio to receive
tapentadol IR (50 or 100 mg every 4-6 hours as needed; up to 600 mg/day)
or oxycodone HCl IR (10 or 15 mg every 4-6 hours as needed; up to 90
mg/day). Pain intensity over the 24 hours prior to each visit was
recorded from the date of the first study drug intake through the last
visit using an 11-point numerical rating scale (0="no pain," 10 "worst
possible pain"). Tolerability was assessed starting on the day of the
first intake of study drug and concluded 2 days after the final study
drug intake.

Results:

[0087]A total of 679 patients in the tapentadol IR group and 170 patients
in the oxycodone HCl IR group were included in the efficacy and safety
analyses. The pain intensity scores were similar between the groups over
time. Mean baseline pain intensity scores were 7.0 for the tapentadol IR
group, and 7.2 for the oxycodone HCl IR group. These values decreased at
the end of the double-blind period to 4.9 and 5.2 for the tapentadol IR
and oxycodone HCl IR groups, respectively. The most common treatment
emergent adverse events were nausea, vomiting, dizziness, constipation,
headache, and somnolence. Patients in the tapentadol IR group had
significantly (P<0.001 for all measures) lower incidences of nausea
(18%), vomiting (17%), and constipation (13%), compared with the
oxycodone HCl IR group (nausea, 29%; vomiting, 30%; constipation, 27%),
while the incidences of somnolence, dizziness, and headache were similar
between groups. Serious treatment emergent adverse events were reported
by 0.7% and 1.8% of the patients in the tapentadol IR and oxycodone HCl
IR groups, respectively. These were not judged by the investigator to be
related to the study drug.

[0089]Analyses included 679 and 170 patients in the tapentadol IR and
oxycodone HCl IR groups, respectively. Opioid-experienced patients
(taking opioids at least 5 days/week for 30 days before screening) made
up 49.0% and 48.2% of patients in the tapentadol IR and oxycodone HCl IR
groups, respectively. Mean pain scores decreased from baseline to study
end for the tapentadol IR (7.0 to 4.9) and oxycodone HCl IR 7.2 to 5.2)
groups, respectively. The most common treatment-emergent adverse events
(TEAEs) were nausea, vomiting, dizziness, constipation, headache, and
somnolence. Significantly (P<0.001) fewer gastrointestinal TEAEs
occurred in the tapentadol IR group (nausea, 18%; vomiting, 17%;
constipation, 13%) than in the oxycodone HCl IR group (nausea, 29%;
vomiting, 30%, constipation, 27%), while the rates of headache,
dizziness, and somnolence were similar in both groups. Generally,
non-opioid-experienced patients had more TEAEs, but patients taking
tapentadol IR were less likely to experience adverse events within this
subgroup compared with oxycodone HCl IR patients. For non-experienced
patients, vomiting occurred in 18% and 39% in the tapentadol IR and
oxycodone HCl IR groups, respectively, while nausea was reported by 22%
and 35% of tapentadol IR and oxycodone HCl IR patients, respectively. In
opioid-experienced patients, 16% and 21% reported vomiting in the
tapentadol IR and oxycodone HCl IR groups, respectively, while nausea
occurred in 14% of patients in the tapentadol IR group and 23% in the
osycodone HCl IR group. Prior opioid experience did not reduce the
incidence of constipation in either the tapentadol IR (opioid-experience,
17%; non-experienced, 14%) or oxycodone HCl IR (opioid-experienced, 27%;
non-experienced, 27% groups.

[0090]674 randomly assigned patients received doses of placebo, tapentadol
IR 50 or 75 mg, or oxycodone HCl IR 10 mg every 4 to 6 hours during
waking hours. Study endpoints included the sum of pain intensity (SPID)
over 5 days (primary endpoint), tolerability assessments, and analyses of
age and gender to examine potential differences among subsets of the
study population.

Results:

[0091]666 randomly assigned patients were included in the safety analyses;
659 were included in the efficacy analyses. Tapentadol IR 50 and 75 mg
showed significant improvements in pain, compared with placebo, bases on
5-day SPID scores (P<0.001). The oxycodone IR 10 mg group also showed
significant improvements in 5-day SPID scores (P<0.001) compared with
the placebo group, which validated assay sensitivity. Based on
pre-specified criteria for 5-day SPID, tapentadol IR 50 and 75 mg were at
least as effective as oxycodone HCl IR 10 mg. 5-day SPID scores in all
active treatment groups were similar between patients <65 and
≧5 years old as well as between male and female subgroups. Common
adverse events included gastrointestinal (GI) and central nervous system
disorders. Overall, the incidence of GI adverse events showed a dose
response relationship for the tapentadol IR 50 and 75 mg groups (29% and
40%, respectively) that was lower than oxycodone HCl IR 10 mg (69%).
These trends were also evident within the subgroups. Patients <65 and
≧65 reported fewer GI adverse events for tapentadol IR 50 mg (25%
and 36%, respectively) than 75 mg (42% and 38%, respectively), and both
were less than oxycodone HCl IR 10 mg (66% and 74%, respectively). The
incidence of GI adverse events reported by the male and female subgroups
were 21% and 39%, respectively for tapentadol IR 50 mg, 28% and 54%,
respectively for tapentadol IR 75 mg, compared with 58% and 81%,
respectively for oxycodone HCl IR 10 mg.

Conclusions:

[0092]The clinical data demonstrate the efficacy of tapentadol IR for the
treatment of chronical pain due to osteoarthritis. As regards
gastrointestinal adverse events the clinical data shows an improved
tolerance of tapentadol compared to oxycodon HCl.

[0093]The foregoing description and examples have been set forth merely to
illustrate the invention and are not intended to be limiting. Since
modifications of the described embodiments incorporating the spirit and
substance of the invention may occur to persons skilled in the art, the
invention should be construed broadly to include all variations within
the scope of the appended claims and equivalents thereof.